tbuckley/cabot-search huggingface dataset:
Benefits of measuring urinary protein/creatinine ratio in lenvatinib treatment for unresectable hepatocellular carcinoma.
Authors: Koki Morishita, Hidetaka Suzuki, Junko Tauchi, Misaki K Takeno, Shota Yamaguchi, Kanae Inoue, Tomonao Taira, Hiroki Eguchi, Kei Okumura, Taro Shibuki, Tomoyuki Satake, Kazuo Watanabe, Hiroshi Imaoka, Mitsuhito Sasaki, Shuichi Mitsunaga, Toshikatsu Kawasaki, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2023)

529 Background: Proteinuria is a well-known lenvatinib (LEN)-associated adverse event. The standard management of proteinuria includes measurement of the urinary protein/creatinine ratio (UPCR) in patients with a qualitative result for proteinuria of ≥1+. Although several studies have shown a good correlation of the UPCR with the qualitative result, it remains unclear how the management of proteinuria by measuring the UPCR might affect the clinical outcomes. This study was aimed at revealing the effect of measuring UPCR on the treatment efficacy and safety in unresectable hepatocellular carcinoma (uHCC) patients receiving LEN. Methods: We retrospectively analyzed the data of uHCC patients who received LEN between March 2018 and February 2022 at National Cancer Center Hospital East. Patients in the UPCR group were monitored by measurement of the UPCR when the qualitative result was ≥2+, while those in the non-UPCR group were not. LEN was withdrawn when the UPCR was ≥3.5 in the UPCR group, and the qualitative result for proteinuria was ≥3+ in the non-UPCR group. Results: A total of 89 patients were included in this study, of which 39 had a qualitative result for proteinuria of ≥2+. Of these 39 patients with proteinuria, 22 were classified into the UPCR group and the remaining into the non-UPCR group. Of the 209 qualitative results of ≥2+ in the UPCR group, 10 (4.8%) corresponded to a UPCR of ≥3.5. The relative dose intensity of LEN during the first 8 weeks was significantly higher in the UPCR group (64.4%) than in the non-UPCR group (52.8 %, p = 0.047). The time to treatment failure was 12.6 months (95% CI, 6.3-16.9) in the UPCR group and 5.5 months (95% CI, 2.1-11.0) in the non-UPCR group (p = 0.125). The rate of change in eGFR from the baseline to the end of treatment was not significantly different between two groups. Conclusions: Measurement of UPCR might contribute to avoiding unnecessary interruption of LEN, because the UPCR values in most patients were below 3.5.
Presence and impact of antidrug antibodies (ADAs) to tremelimumab (T) or durvalumab (D) in the phase 3 HIMALAYA study of unresectable hepatocellular carcinoma (uHCC).
Authors: Oxana V. Crysler, Mark Yarchoan, Junji Furuse, Peter R. Galle, Wattana Sukeepaisarnjaroen, Nguyen Tien Thinh, Gianluca Masi, Ho Yeong Lim, Maria Varela, Charu Gupta, Mallory Makowsky, Alejandra Negro, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2023)

551 Background: ADAs to immune checkpoint inhibitors may decrease antitumor activity in HCC. Reported rates of treatment-emergent ADAs (TE-ADAs) vary from 1.5% for pembrolizumab and 8.6% for nivolumab to 54.1% for atezolizumab across indications (Enrico et al. Clin Cancer Res 2020). In the global, Phase 3 HIMALAYA study (NCT03298451) in uHCC, the STRIDE regimen (Single T Regular Interval D) significantly improved overall survival vs sorafenib (S); D monotherapy was noninferior to S (Abou-Alfa et al. NEJM Evid 2022). Here, we analyzed ADAs to T and D in HIMALAYA. Methods: Prespecified secondary analyses assessed the presence of ADAs to D and T before the first study dose (baseline), once during treatment and once after treatment discontinuation. For participants (pts) who were ADA-positive at any visit (ADA+), presence of neutralizing antibodies (nAbs) was also assessed. TE-ADA+ was defined as pts with a positive post-baseline sample only or pts with an ADA titer that increased ≥4-fold following treatment. ADA negative (ADA-) was defined as pts with no positive sample at any visit, at baseline or post-baseline. Objective response rate (ORR; RECIST v1.1, inc. unconfirmed), overall survival (OS) and treatment-related adverse events (TRAEs) were evaluated in ADA subgroups. Results: The frequency of ADAs to D was similar in the STRIDE (T+D) and D arms: 8.2% (24/294) and 7.1% (20/282) of pts, respectively, were ADA+ to D; 3.1% (9/294) and 2.8% (8/282) of pts, respectively, were TE-ADA+ to D; and 1.7% (5/294) and 0.7% (2/282) of pts, respectively, had nAbs to D. In the STRIDE arm, 15.9% (29/182) of pts were ADA+ to T, 11.0% (20/182) of pts were TE-ADA+ to T, and 4.4% (8/182) of pts had nAbs to T. Although the number of pts was small, in the STRIDE arm, ORR was 11.1% (1/9) in pts TE-ADA+ to D, 35.0% (7/20) in pts TE-ADA+ to T and 23.9% (94/393) in the full analysis set (FAS). In the D arm, ORR was 25.0% (2/8) in pts TE-ADA+ to D and 18.5% (72/389) in the FAS. OS for pts TE-ADA+/nAb+ to D or T in the D and STRIDE arms was consistent with the FAS. In both arms, TRAE and Grade 3/4 TRAE rates were not increased in the ADA+ vs ADA- groups (Table) and were generally consistent with the overall population. Conclusions: In HIMALAYA, the rates of TE-ADAs and nAbs to D and T were low (≤11%). The presence of ADAs did not appear to impact clinical efficacy or safety of STRIDE or D monotherapy in the small number of ADA+ pts. These results support a low risk of ADAs for STRIDE or D in uHCC. Clinical trial information: NCT03298451 . [Table: see text]
Prospective cohort study of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: The HiSCO-04 study.
Authors: Manabu Shimomura, Satoshi Ikeda, Masahiro Nakahara, Tomohiro Adachi, Yasufumi Saitoh, Yosuke Shimizu, Kazuhiro Toyota, Yasuyo Ishizaki, Masanori Yoshimitsu, Yuji Takakura, Wataru Shimizu, Daisuke Sumitani, Shinya Kodama, Masahiko Fujimori, Mamoru Oeda, Hironori Kobayashi, Hideki Ohdan
Journal: Journal of Clinical Oncology (2023)

102 Background: There was no consensus about the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥80 years who underwent curative resection. We conducted a prospective cohort study of patients with stage III CRC aged ≥80 years who underwent curative resection together with a phase II feasibility study on uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy. Methods: This multi-institutional prospective cohort study involved 17 institutions in Hiroshima, Japan. Patients with stage III CRC aged ≥80 years who underwent curative resection were enrolled. We prospectively collected the clinicopathological data including the status of the administration of adjuvant chemotherapy, follow-up, and oncological outcomes. The primary endpoint was three-year disease-free survival (DFS) and secondary endpoints were three-year overall survival (OS) and relapse-free survival (RFS). Results: From December 2013 to June 2021, 214 patients were examined. There were 99 men and 115 women with the median age of 84 years (range, 80–101). There were stage IIIA diseases in 27 cases, IIIB in 158 cases, and IIIC in 29 cases (TNM eighth edition). Median follow-up time was 42.5 months (range, 0.16–84.04 months). Thirty-six patients died due to CRC and 30 patients died due to other causes. There was recurrence in 58 cases (27.1%), and any treatment was administrated in 29 patients. Secondary cancers were observed in 17 cases in the follow-up period. The three-year DFS was 63.6%, 3-year OS was 76.9%, and 3-year RFS was 63.1%. Adjuvant chemotherapy was administrated in 64 cases and the completion rate was 53%. Adjuvant chemotherapy tends not to be given in older age, poor performance status, high Charlson comorbidity index, and low preoperative prognostic nutritional index. In a study of 80 patients adjusted for background factors using propensity score matching, it was shown that patients who completed planned treatment have improved DFS. Conclusions: Completion of adjuvant chemotherapy may improve prognosis in CRC patients over 80 years of age, but the number of patients who would benefit was limited. Appropriate dose adjustment and supportive care for postoperative adjuvant chemotherapy are important, as well as the need to identify patient groups who will not tolerate chemotherapy.
Total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A real-world experience.
Authors: Erika Ruiz-Garcia, Rogelio Cuervo Cmapos, Juan Carlos Falcon, German Caderillo-Ruiz, Maria del Consuelo Diaz Romero, Marytere Herrera, Sayako Mariana Miyagui-Adame, Itzel Vela, Nora Alvarez, Leonardo Lino-Silva
Journal: Journal of Clinical Oncology (2023)

62 Background: The standard treatment of locally advanced rectal cancer (LARC defined as T3-T4, N+) consists of giving chemoradiation therapy (CT/RT) followed by total mesorectal excision (TME) after 6-8 weeks followed by chemotherapy (CT) adjuvant. Recently, total neoadjuvant therapy (TNT) has shown greater efficacy in terms of increasing the rate of complete pathological response (pCR) and reducing local and systemic relapse, in addition to increasing sphincter preservation. The objective of this study was to know the percentage of pCR (ypT0N0) presented by Mexican patients with LARC treated at the National Cancer Institute (INCan) with the TNT (implemented in 2019) vs. standard treatment. Methods: An observational, analytical, and retrospective study was carried out, with a non-probabilistic sampling of patients with LARC treated at INCan from 2016 to 2021. Comparisons of continuous numerical variables for independent samples were analyzed using Student's t test or Mann-Whitney U test (depending on its distribution). To examine the association in the discrete variables, the X2 test or Fisher's exact test (according to the case) was used. The association between continuous variables was analyzed using Pearson's or Spearman's correlation coefficients according to the distribution. Statistical difference was considered significant when p &lt; 0.05. The analysis was performed with the statistical package SPSS v26.0. Results: 286 patients were analyzed (N=76 corresponded to TNT), mean age was 57 years, 43% were female, 84% were stage III and 64% had a lower rectal tumor. Complete TME was present at 78.9%. The pCR rate was 45.16% with TNT vs. 22.39% with CT/RT (RR 0.70, 95% CI (0.56-0.90) p= 0.001). 18% recurrences and/or progressions were identified in the TNT group vs. standard treatment (28.2%) with a tendency to statistical significance (RR 0.6 95% CI (0.36-1.08) p= 0.08). 7% mortality was reported with TNT vs. 19% with standard therapy (RR of 1.15, CI 95% (1.05-1.26) p= 0.013). Conclusions: TNT was shown to increase the percentage of complete pathological responses compared to chemoradiotherapy treatment in real-world population attended at INCan. The follow-up of these patients is still short to know the final impact of TNT in terms of relapse-free survival and overall survival.
RELATIVITY-123: A phase 3, randomized, open-label study of nivolumab (NIVO) + relatlimab (RELA) fixed-dose combination (FDC) versus regorafenib or trifluridine + tipiracil (TAS-102) in later-line metastatic colorectal cancer (mCRC).
Authors: Kynan Feeney, Warren Lance Joubert, Rodolfo Eduardo Bordoni, Sunil Babu, Sathiya Marimuthu, Bill Hipkin, Liping Huang, Rachel Tam, Mirelis Acosta Rivera
Journal: Journal of Clinical Oncology (2023)

TPS278 Background: The standard of care (SoC) for first-line management of non-microsatellite instability-high/deficient mismatch repair (non-MSI-H/dMMR; also referred to as microsatellite-stable/proficient MMR) mCRC includes systemic chemotherapy and targeted agents that improve overall survival (OS). However, in patients (pts) with later-line disease, current SoC treatments (including regorafenib and TAS-102) are associated with poor responses (objective response rates [ORR] &lt; 2%) that are not durable, limited OS (6.4-7.1 months) and substantial toxicity. Immunotherapies targeting programmed death (PD)-1 show promising efficacy in pts with MSI-H mCRC; however, single-agent immunotherapy does not provide benefit for pts with non-MSI-H/dMMR mCRC. Therefore, additional treatment options with an improved benefit-risk profile in pts with later-line non-MSI-H/dMMR mCRC are needed. Emerging data suggest that dual inhibition of LAG-3 and PD-1 has the potential to boost immune surveillance and elicit durable responses in non-MSI-H/dMMR mCRC. RELA is a human immunoglobulin G4 lymphocyte-activation gene 3 (LAG-3)-blocking antibody that enhances the antitumor immune response. Here we describe the RELATIVITY-123 study investigating NIVO + RELA FDC in later-line mCRC. Methods: RELATIVITY-123 (NCT05328908) is a phase 3, randomized (1:1), open-label study to assess NIVO + RELA FDC versus regorafenib or TAS-102 in adult pts with later lines of non-MSI-H/dMMR mCRC. Inclusion criteria include metastatic or recurrent unresectable CRC, recent progression following 1–4 prior lines of treatment (or documented intolerance of prior systemic chemotherapy regimens), ECOG performance status ≤ 1, and measurable disease per RECIST version (v) 1.1. Exclusion criteria include confirmed MSI-H/deficient mismatch repair, prior treatment with an immunotherapy, regorafenib, or TAS-102 and history of significant cardiovascular disease, interstitial lung disease/pneumonitis, or autoimmune disease. Dual primary endpoints are OS in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. Secondary endpoints include ORR, progression-free survival, and duration of response by blinded independent central review and investigator per RECIST v1.1, safety, and time until definitive deterioration-physical function and -quality of life in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. The study initiated in April 2022 and is enrolling globally. Clinical trial information: NCT05328908 .
Frequency and outcomes of <i>BRAF</i> alterations identified by liquid biopsy in metastatic non-colorectal gastrointestinal cancers.
Authors: Amit Mahipal, Leslie Bucheit, Nicole Zhang, Jing Jiang, Lesli A. Kiedrowski, Sakti Chakrabarti
Journal: Journal of Clinical Oncology (2023)

808 Background: The impact of BRAF V600E, a known poor prognostic factor in metastatic colorectal cancer (CRC), has not been assessed broadly in non-CRC gastrointestinal (GI) cancers including pancreatic (PC), gastric/gastroesophageal (GC), hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In view of recent tumor-agnostic approval of a BRAF V600E inhibitor, it is important to determine the prevalence and impact of BRAF alterations on non-CRC GI cancer patients (pts). Methods: Genomic results from pts with PC, GC, HCC, or CCA tested with Guardant360 (G360, Guardant Health) as part of clinical care from June 2019 – June 2022 were retrospectively queried. Prevalence of characterized nonsynonymous BRAF genomic alterations (GA) was analyzed; differences between cancer types was assessed using the Chi-squared test. The GuardantINFORM database with aggregated commercial payer health claims and de-identified records from over 243,000 individuals with G360 results was used to derive real-world overall survival (rwOS), reported in months, calculated from diagnosis of metastatic cancer; differences between cancer types were compared using log-rank tests. Results: 23,069 patients were included: PC:49%; GC:24%; CCA:20%; HCC:6%. Pts were more likely to be male (p&lt;0.01). PC/HCC pts were tested more often at new diagnosis (vs at disease progression) than GC/CCA (p=0.02, p&lt;0.01, respectively). BRAF GAs were identified in 2.9%, comparable to tissue-based datasets (MSK-IMPACT: 2.4%); 21% of BRAF GAs were V600E (0.6% prevalence overall). PC/CCA pts were more likely to have BRAF GAs than the overall cohort (p&lt;0.01); they also had more BRAF V600E GAs (p&lt;0.01). rwOS differed by cancer type and BRAF status (Table). Notably, CCA pts with BRAF V600E had superior rwOS compared to CCA pts without BRAF findings (p=0.02). rwOS is not reported for HCC due to small n. Conclusions: Identification of BRAF GAs and V600E in the non-CRC GI population by liquid biopsy is similar to rates observed in tissue-based testing and may be reliably used to assess BRAF status. BRAF GAs and subtypes have mixed prognostic implications on survival for PC/CCA/GC patients that warrants further exploration. [Table: see text]
A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613.
Authors: Kanwal Pratap Singh Raghav, Katherine A Guthrie, Scott Kopetz, Benjamin R. Tan, Crystal S. Denlinger, Marwan Fakih, Michael J. Overman, Arvind Dasari, Larry R. Corum, Lee G. Hicks, Mital Patel, Benjamin T Esparaz, Syed Mohammad Ali Kazmi, Nitya Alluri, Sarah Colby, Sepideh Gholami, Philip Jordan Gold, E. Gabriela Chiorean, Howard S. Hochster, Philip Agop Philip
Journal: Journal of Clinical Oncology (2023)

140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio &gt; 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m 2 + irinotecan 180 mg/m 2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (&gt;5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]
Deep learning–assisted colonoscopy images for prediction of mismatch repair deficiency in colorectal cancer.
Authors: Jiancong Hu, Huabin Hu, Yue Cai, Xijie Chen, James Liao, Ming Han, Lishuo Shi, Junguo Chen, Wei Liu, Mingli Su, Chao Wang, Yan Huang, Xiaosheng He, Ping Lan, Yanhong Deng
Journal: Journal of Clinical Oncology (2023)

24 Background: Deficient mismatch repair (or microsatellite instability) is a major predictive biomarker for the efficacy of immune checkpoint inhibitors of colorectal cancer. However, routine testing is time-consuming and incur substantial costs. We developed and validated a deep learning-based classifiers (MMR-Scopy) to detect mismatch repair-deficient status from routine colonoscopy images. Methods: We retrospectively obtained the colonoscopy images from the imaging database at Endoscopic Center of the Sixth Affiliated Hospital of Sun Yat-sen University. Colorectal cancer images from patients that had undergone colonoscopy procedures, surgery and the mismatch repair immunohistochemistry test were eligible for this study. Colonoscopy images from a prospective trial (Neoadjuvant PD-1 blockade by toripalimab with or without celecoxib in mismatch repair-deficient or microsatellite instability-high locally advanced colorectal cancer, PICC) were used to test MMR-Scopy. The primary outcome was dMMR status. The primary performance metrics were accuracy, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUROC). Results: A total of 5226 eligible images from 892 tumors from the consecutive patients were utilized to develop and validate the deep learning model. 2105 CRC images from 306 tumors were randomly selected to form model development dataset with a class-balanced approach. 3121 images of 488 pMMR tumors and 98 dMMR tumors were used to form the independent dataset. The MMR-Scopy model achieved an AUROC of 0.948 (95% CI 0.919- 0.977) on the test dataset. On the independent validation dataset, the AUROC was 0.807 (0.760- 0.854), and the NPV in was 94.2% (95% CI 0.918-0.967). On the PICC dataset, the model identified 29 tumors among the 33 dMMR tumors (87.88%). Conclusions: MMR-Scopy achieved a high NPV in detecting dMMR colorectal cancers. This model might serve as an automatic screening tool, one that might potentially assist doctors in determining a new treatment strategy. [Table: see text]